Antiretroviral Therapy for Acute (Primary) HIV

Professor of Medicine
Division of Infectious Diseases
Clinical Director
Northwest AIDS Education and Training Center
University of Washington School of Medicine

Learning Objectives:

Discuss the pros and cons of initiating antiretroviral therapy for acute HIV infection.

Understand the relationship of acquisition of resistant strains of HIV and response to antiretroviral therapy.

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Question

A 22-year-old man presents with a 3-day history of a mononucleosis-like illness that began 9 days after a high-risk sexual exposure with an HIV-infected contact. Laboratory studies subsequently show a negative HIV antibody ELISA test and a HIV RNA level of 868,000 copies/ml. Further testing shows a CD4 cell count of 568 cells/mm3. This newly infected individual receives extensive counseling regarding his new diagnosis of HIV and, in the process of this discussion, the patient asks whether he should now start treatment for his HIV disease.

Which of the following statements is TRUE regarding antiretroviral therapy for acute (primary) HIV infection?

Fewer than 30% of persons with acute HIV infection treated with antiretroviral therapy will achieve an HIV RNA level less than 400 copies/ml, mainly as a result of the very high HIV RNA levels and the weak immune response at this stage.

Incorrect

Although HIV RNA levels are typically very high with acute HIV infection, available data suggest that treatment of primary infection with a 3- or 4-antiretroviral drug combination regimen generally reduces HIV RNA levels at least as well as with treatment of chronic infection.

Transmission of antiretroviral-resistant HIV has been documented and persons who acquire antiretroviral resistant HIV are more likely to have failure with antiretroviral therapy.

Correct

Transmission of resistant HIV has clearly been documented with multiple different routes of exposure. Recent studies have shown that persons who acquire resistant HIV are more likely to fail antiretroviral therapy, with a longer time to viral suppression and a shorter time to virologic failure.

More than 90% persons with acute HIV who initiate 4-drug antiretroviral therapy prior to seroconversion (and continue therapy for 24 months) will eventually maintain long-term virologic control without antiretroviral therapy.

Incorrect

Although early data were promising using this approach, long-term follow-up has shown that most of the patients eventually failed to maintain control of HIV.

Antiretroviral therapy with a 3-drug regimen initiated within 180 days of acquiring HIV allows for a step-down to a 2-drug regimen after 1 year of therapy

Incorrect

Based on currently published data, there is no evidence that antiretroviral therapy given immediately during or prior to HIV seroconversion allows for a step-down to a less aggressive antiretroviral regimen.

This figure illustrates the concept of using treatment interruptions after initiating highly active antiretroviral therapy (HAART) to augment HIV immune responses in patients with early HIV infection. In this protocol, patients with early HIV infection received HAART until their HIV RNA levels were below 400 copies/ml for 2 months and then reinitiated antiretroviral therapy if the HIV RNA levels exceeded 5,000 copies/ml for 3 weeks or 50,000 copies/ml for a single value.

In this series, 14 patients received potent antiretroviral therapy during acute HIV infection and subsequently underwent supervised treatment interruptions. The graph shows the percentage of subjects who maintained virologic control to less than 5,000 copies/ml for at least 90 days after one, two, or three treatment interruptions.

This graph shows overall resistance rates to any antiretroviral class in persons with acute/early HIV-1 infection in San Francisco during the years 2002 to 2009. Resistance rates ranged from 7% (2003) to 24% (2007).

After initial infection, HIV can undergo the process of back mutation whereby HIV mutations with a high fitness cost would be expected to revert to in the direction of wild type virus whereas those mutations with a low fitness cost to HIV may revert slowly or not at all.

Figure 6 - 2014 HHS Guidelines for the Use of Antiretroviral Therapy in Acute HIV Infection

Image A. Antiretroviral Therapy Recommendations

Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Considerations for Antiretroviral Use in Special Patient Populations. Acute and Recent (Early) HIV Infection. May 1, 2014.

Source: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 1, 2014.

Investigators have performed more than 35 studies involving the initiation of antiretroviral treatment during early HIV infection, with early HIV infection defined as acute (primary) HIV infection or recent HIV infection (within 6 months of HIV seroconversion). These studies have included uncontrolled trials, non-randomized comparative trials, and randomized trials and have differed significantly with respect to the antiretroviral regimens, exact timing of starting therapy, and the duration of therapy.[1,2,3,4,5] Three extensive reviews have analyzed available data related to this topic from trials published prior to 2010.[1,2,3] In addition, investigators recently completed the Short Pulse Antiretroviral Therapy at HIV Seroconversion (SPARTAC) trial, the largest randomized controlled trial involving patients with primary HIV infection.[4] In this trial, investigators randomized 372 patients with early HIV infection to one of three treatment arms: 12 weeks of antiretroviral therapy, 48 weeks of antiretroviral therapy, or no antiretroviral therapy.[4] Based on a median follow-up of 4.3 years, the investigators concluded CD4 cell counts declined more slowly and viral set point was lower in the patients who received the 48-week treatment course when compared with the other arms; the most pronounced benefit occurred in patients who started antiretroviral therapy within 12 weeks of HIV seroconversion. No significant differences were observed in the three arms with likelihood of AIDS, death, or serious adverse events. Based on the available data from reviews and the SPARTAC trial, the following conclusions can be made. First, antiretroviral therapy given during acute HIV infection improves short-term CD4 cell count recovery during early HIV infection when compared with no antiretroviral therapy in this setting.[5,6,7] Second, treatment with a 3- or 4-drug regimen during acute infection generally reduces HIV RNA levels at least as well as with treatment during chronic infection, but the optimal regimen remains unknown.[8,9,10,11] Third, antiretroviral therapy initiated during acute HIV and given for short-term (typically 48 weeks or less) followed by discontinuation of therapy has produced mixed results with regard to lowering the viral setpoint.[1,4,12,13] Fourth, several studies have shown that antiretroviral therapy initiated during acute infection slows the rate of CD4 count decline and thus may prolong the need for subsequent initiation of antiretroviral therapy.[4,12,14] Last, although several studies have shown initiating antiretroviral therapy during acute (or early) HIV may reduce the short-term incidence of HIV-related complications, the trials have not clearly answered the question whether this approach provides a long-term clinical advantage when compared with the standard approach of initiating therapy in patients with chronic HIV infection based on a decline below a CD4 cell count threshold.[5,9]

Studies Involving Structured Treatment Interruptions

Several clinical trials have shown that antiretroviral therapy given during acute HIV infection augments HIV-specific T-cell responses and enhances recovery of the CD4 Vbeta T-cell repertoire.[6,15,16,17] These findings, as well as data from other studies, spurred an interest in determining whether these treatment-related immune responses could improve immune-based control of HIV on a long-term basis. To this end, several groups have aggressively treated patients with acute or early HIV infection, maintained virologic control for 1 to 3 years with continuous antiretroviral therapy, and then introduced a series of structured treatment interruptions in an effort to augment the immune response and control HIV without antiretroviral therapy (Figure 1). Using this protocol, investigators have experienced mixed results.[11,15,18] In one study, 11 (79%) of 14 patients maintained HIV RNA levels less than 5,000 copies/ml for at least 90 days after one, two, or three treatment interruptions, but longer-term follow-up of these patients showed only 21% of patients maintained control of HIV 2 years after stopping antiretroviral therapy (Figure 2).[19] Based on the longer-term follow-up of these patients, the initial enthusiasm for this approach has waned.

Studies Involving Immune Modulators

Several groups of investigators have combined an immune modulator with antiretroviral therapy during the treatment of acute HIV infection. The adjunctive use of the immune modulators cyclosporin A or interleukin-2 has produced impressive increases in CD4 cell counts,[10,20] but the long-term effects and clinical benefits of this approach in the setting of acute HIV infection remain unknown. In a study involving macaques, investigators examined the immune response to acute infection with simian immunodeficiency virus (SIV) and their findings provided insight into the beneficial and harmful effects of the host immune response to acute infection.[21,22] In the largest trial involving cyclosporin in early HIV infection, investigators randomized 54 individuals with acute and early HIV infection to receive antiretroviral therapy and cyclosporin or antiretroviral therapy alone; they concluded that adjunctive therapy with cyclosporin did not provide virologic or immunologic benefit when used in this setting.[23] Investigators have also shown interest in using an HIV vaccine in the setting of acute infection to further enhance immune responses. In one such study, 11 subjects with acute HIV infection received antiretroviral therapy plus at least four adjunctive HIV vaccine injections and the antiretroviral therapy was continued for a median of 3.2 years.[11] Although strong HIV cell-mediated immune responses were induced, viral rebound occurred in all patients, and none maintained an HIV RNA less than 500 copies/ml after discontinuing antiretroviral therapy.

Resistance in Newly Infected Persons

Multiple studies have clearly documented transmission of drug-resistant HIV, including through sexual, parenteral, and vertical routes.[24,25,26,27,28] Studies from North America and Europe report that an estimated 6 to 16% of transmitted HIV will show resistance to at least one antiretroviral medication and 3 to 5% of transmitted virus has resistance to multiple classes of antiretroviral drugs.[29] A study conducted in San Francisco examined HIV resistance patterns in persons with acute or early HIV during the years 2002 to 2009 and found substantial resistance throughout this period (Figure 3), including variable and changing class-specific HIV patterns (Figure 4).[30] In addition, transmitted resistance has been associated with suboptimal response to antiretroviral therapy if the transmitted drug resistance was not known at the time the initial regimen was selected.[25,28,31] Early data suggested that transmitted resistant HIV would not continue to be detectable on a genotype after 1 to 2 years in the absence of antiretroviral therapy selective pressure (as a result of the decreased replicative capacity of resistant HIV compared with wild-type HIV).[28] Subsequent studies, however, have shown that some genotypic mutations acquired as transmitted HIV can persist for years among untreated patients.[28,32] The May 2014 Health and Human Services (HHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents recommends performing resistance testing for persons with acute or early HIV infection, regardless of whether the decision is made to initiate therapy.[29] Although some transmitted mutations may persist for years, those mutations that have a high fitness cost for HIV may back mutate and strains of HIV will display progressively fewer mutations on the genotype (Figure 5). Similarly, wild-type HIV may replicate more rapidly outpace strains with mutations. Thus, the highest yield of detecting transmitted resistant HIV occurs soon after HIV infection. If therapy is deferred, the guidelines suggest considering repeat resistance testing prior to initiating antiretroviral therapy, given that patients may possibly acquire resistant HIV in the interim.[29] Genotype testing is preferred for the resistance testing.

Recommendations Regarding Antiretroviral Therapy

The May 2014 HHS antiretroviral guidelines highlight the potential advantages and disadvantages of initiating therapy during acute or recent HIV infection.[29] Early intervention with effective antiretroviral therapy for individuals with acute or recent HIV infection could theoretically decrease the severity of the primary infection illness, lower the initial viral load set point, slow disease progression rate, enhance recovery of CD4 cell populations, reduce the rate of viral mutations as a result of suppressing viral replication, and decrease the risk for transmission of HIV.[29] On the other hand, treatment of acute infection could adversely impact the patient's quality of life, expose the patient to the risks of antiretroviral therapy without a clearly demonstrated benefit, enhance the potential for adherence problems because of a lack of adequate time to prepare for starting medications, and increase the likelihood of developing antiretroviral drug resistance that could limit options for subsequent treatment of chronic HIV infection.[29] Thus, the guidelines recommend that treatment in this setting should be considered optional at this time (Figure 6).[29] The International Antiviral Society-USA guidelines recommend treatment of symptomatic primary HIV infection.[33] Several investigators have noted the high risk of HIV transmission that occurs from persons with acute or early HIV infection.[34] More recently, treatment of HIV-infected individuals with antiretroviral therapy has been established as an important means of preventing HIV transmission.[35] Given the hyperinfectious state of acute HIV, some experts have advocated for the treatment of patients with early HIV from a public health standpoint to reduce forward transmission of HIV.[36] If treatment is initiated for a patient with early HIV infection, the goal should be to suppress HIV RNA to undetectable levels. Patients with acute or recent HIV infection should receive a regimen recommended for the treatment of chronically infected persons, using genotype data to guide the choice of therapy.[29] Many experts would avoid the use of a non-nucleoside-based regimen until genotype resistance results were known and instead use a ritonavir-boosted protease inhibitor-based regimen. For example, transmission of virus with the K103N mutation could lead to rapid virologic failure if an efavirenz (Sustiva)-based regimen was used prior to the return of the genotypic results. In one study of treatment for acute HIV infection, investigators reported 9 (18%) of 50 persons who received abacavir (Ziagen) developed an abacavir hypersensitivity reaction.[37] Based on this report, it would seem prudent to ensure that a patients has a negative HLA-B*5701 test prior to starting abacavir as part of a regimen to treat acute HIV infection. The optimal duration of therapy for patients with early HIV infection remains unknown.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Considerations for Antiretroviral Use in Special Patient Populations. Acute and Recent (Early) HIV Infection. May 1, 2014.